Regulation of Feto-Maternal Barrier by Matriptase- and PAR-2-Mediated Signaling Is Required for Placental Morphogenesis and Mouse Embryonic Survival
Figure 1
Combined loss of matriptase/prostasin- and PAR-2-dependent proteolytic pathways leads to embryonic lethality.
(A). Matriptase haploinsufficiency decreases survival of PAR-2-deficient mice. Genotype distribution among 706 pre-weaning offspring from interbred F2rl1+/−×F2rl1+/−;St14+/− mice. A normal distribution of F2rl1 alleles was observed in St14+/+ background, whereas the number of F2rl1−/− mice heterozygous for matriptase was significantly decreased (P<0.0001). (B). Genotype distribution among 272 newborn offspring from interbred F2rl1+/−;St14+/−×F2rl1+/−;St14+/− mice. F2rl1 alleles were found in the expected Mendelian ratio in St14+/+ mice, whereas numbers of F2rl1−/−;St14+/− and F2rl1+/−;St14−/− mice was significantly reduced, and no F2rl1−/−;St14−/− mice were observed (P<0.0001). (C). Relative prenatal survival of PAR-2-deficient (F2rl1−/−, blue bars) and matriptase-deficient (St14−/−, green bars) mice shown in (B) as a function of gene dosage of St14 and F2rl1 genes, respectively. Survival of PAR-2-deficient animals decreased from 90% in St14+/+ background, to 40% in St14+/− and 0% in St14−/− background. Similarly, survival of matriptase-deficient mice decreased from 73% in F2rl1+/+ animals to 35% in F2rl1+/− and 0% in the PAR-2-deficient F2rl1−/− animals. (D). Genotype distribution among 247 newborn offspring from interbred F2rl1+/−;Prss8+/−×F2rl1+/−;Prss8+/− mice. F2rl1 alleles were found in the expected Mendelian ratio in Prss8+/+ mice, whereas numbers of F2rl1−/−;Prss8+/− and F2rl1+/−;Prss8−/− mice was significantly reduced, and no F2rl1−/−;Prss8−/− mice were observed (P<0.0005). (E, F). Survival of F2rl1−/−;St14−/− (E) and F2rl1−/−;Prss8−/− (F) embryos before birth, relative to the expected Mendelian distribution. (E). PAR-2/matriptase double-deficient embryos were detected in expected numbers at or before E12.5, followed by a decrease to 59% at E13.5 (N = 251), and 15% at E14.5 (N = 90). No surviving F2rl1−/−;St14−/− animals were detected at or after E15.5. (F). PAR-2 and prostasin double-deficient embryos were detected in expected numbers at E11.5, followed by a gradual decrease to 80% at E12.5 (N = 90), 47% at E13.5 (N = 176), and 17% at E14.5 (N = 68). No surviving F2rl1−/−;Prss8−/− animals were detected at or after E15.5.